17-valerate ester of 6alpha,9alpha-difluoroprednisolone,its compositions and use as an anti-inflammatory agent

ABSTRACT

This invention relates to the new 6 Alpha ,9 Alpha difluoroprednisolone 17-valerate and to pharmaceutical compositions for topical and systemic use of said compound in the treatment of inflammatory conditions.

United States Patent Ercoli et al. 1 Sept. 12, 1972 [54] l7-VALERATE ESTER OF 60:,9a- [56] References Cited DIFLUOROPREDNISOLONE, ITS COMPOSITIONS AND USE AS AN UNITED STATES PATENTS ANTI-INFLAMMATORY AGENT 2,838,499 6/1958 Spero et a1 ..260/239.55 AM e Milan; Rinaldo 3333523 51:32? 3232235255.:11111313326333 came 3,312,590 4/1967 Elks et al ..167/58 [73] Assignee: Warner-Lambert Pharmaceutical 3,383,394 5/1968 Weber et al. ..260/397.45

Company, Morris Plains, NJ. Primary Examiner-Henry A. French [22] Filed J 1970 Attorney-Albert l-l. Graddis, Henry E. Millson, Jr., [211 App]. NO.: 44,560 Frank S. Chow, Neil D. Edwards and Anne M. Kelly Related US. Application Data I 57 ABSTRACT [63] COntinuatiOnin-part of Ser. No. 707,934, Feb. This invention relates to the new 9 1968 abandoneddifluoroprednisolone l7-valerate and to pharmaceutical compositions for topical and systemic use Of said [52] [1.8. CI ..260l397.45, 260123955 D, 424/243 compound in the treatment f i fl t condi [51] Int. Cl ..C07c 169/34 dorm [58] Field of Search ..lMachine Searched Steroids 1 Claim, No Drawings rm-on (H) -o (.0 mt, ulucu,- n, no. r w /5 i This compound shows anti-inflammatory properties particularly high incomparison with those of the known 6d, 9a-difluoroprednisolone and of its 21- esters. The new l7-valerate ester of this inventionpo'ssesses the unusual property of being effective for topical and systemic use as an anti-inflammatory steroid in contrast with the hitherto known l7-alkanoa'te esters of other corticosteroids which are active only when topically'administered. Further the new compound of this invention exerts an anti-inflammatory effect by topical application also higher than other closely analogous l 7-monoesters.

On account of its properties, the 17-valerate of 6a,

, 9a -difluoroprednisolone in the form of pharmaceutical compositions is particularly suited for the topical and systemic treatment of inflammatory conditions and diseases. The compositions of this invention contain the active steroid in intimate admixture with a suitable carrier orzexcipient and may be in solid, semisolid, liquir or viscous form. The active ingredient may be compounded, for example, with the usual carriers for tablets, pellets, suppositories, powders, ointments, lotions, creams, emulsions, aqueous suspensions and other forms particularly suitable for systemic or topical use. For the systemic treatment of arthritis and related diseases the compound may be employed in the form of injectable compositions for intramuscular, subcutaneous or intravenous use.

Preferably, the active steroid is formulated into a topical preparation. The carriers employed are those which have already been proposed for use in manufacturing preparations for topical use, such as for example fats of animal origin and vegetable oils, saturated or unsaturated fatty acids, aluminum stearate, alcohols, polyalcohols, such as for example glycerol, propylene or polyethylene glycols, waxes, aliphatic hydrocarbons or lanolin, together with comparatively high quantities of water. Other carriers which can be used are hydrophilic bases, cholesterol, hydroxycholesterol, vaseline, Vaseline oil, silicones which are physiologically inert, sodium alginate and in addition stabilizing, thickening and coloring agents and perfumes. The compositions of the present invention can also contain preservative or bacteriostatic agents such as for example esters of phydroxy benzoic acid, i.e. methyl-, ethyl-or propyl-p- 'hydroxy benzoate, mercuric derivatives such as for example the merthiolate, or quaternary ammonium derivatives such as for example cetyl-tri'm'ethyl-ammonium bromide, which besides the surface active action possess a good bacteriostatic activity.

Other active ingredients compatible with the new steroid of this invention, such as for example antibiotics, local anesthetics of sulphonamides can also be incorporated in the topical anti-inflammatory compositions if these added properties or characteristics are desired. v I v The l7-valerate ester of 6a,9a-difluoroprednisolone is included in the compositions of this invention in on amount sufficient to produce the desired therapeutic effect upon the inflammatory process or condition. Ad-

vantugeously the compositions will contain the active ingredient in an amount of from 0.0005 percent to 5 percent, and preferably in an amount of from 0.005 percent to 0.5 percent by weight.

The topical compositions of this invention are in- CHzOH lll' onion co --0 oo-Citr,, J

I I 0::- I I wherein R represents a lower alkyl, preferably methyl.

The orthoesterification step is carried out at a temperature ranging from 60 to C and preferably-- around l00-ll0 C for a period of 8-24 hours,

whereby the l7a,2l-orthovalerate of formula lll forms as a mixture of two epimeric' orthoesters. The

orthovalerate thus obtained is then hydrolyzed with a mineral or organic acid to give the l7-monovalerate l.

In order further to illustrate this invention, the following Examples are given.

EXAMPLE 1 A mixture of 2 g of 6a,9a-difluoroprednisolone, 6 cc of methyl orthovalerate and 20 mg of p-toluene-sulfonic acid in 10 cc of dimethylformamide is maintained overnight under nitrogen stream on an oil-bath at 105 C. Then the mixture is neutralized by addition of a few drops of pyridine and concentrated under vacuum to dryness. The residue is taken up with little methanol, filtered and the product crystallized from a methanolmethylene chloride mixture. There is so obtained the l 701,21-(1'-methoxy)-n-pentylidenedioxy 601,90:- difluoro-A--pregnadien-l 1B-ol-3 ,20-dione, which,

' without further purification, is suspended in 10 cc of methanol, treated with 0.5 cc of an aqueous solution of oxalic acid and heated on water bath at 40-50 C:- When the product is completely passed into solution the mixture is concentrated under vacuum. The residue is then shaken with water, the insoluble product filtered off and then dried. The 6a,9a-difluoroprednisolone l7- valerat'e is thus obtained which, when crystallized from acetone-ether, melts at l76-l79 C. Yield 80 percent.

EXAMPLE 2 Anti-inflammatory activity The 'l'7a-valerate of 6a,Qa-difluoroprednisolone was evaluated for its local antiphlogistic effect and for its systemic action in comparison with betamethasone l7- valerate, the compound which is recognized as one of the most topically active anti-inflammatory agents with a low systemic effect.

For this evaluation the recently developed ear irritant test of Tonelli, L.Thibault and I.Ringler (Endocrinology, 77, 625, 1965) was used in order to determine not only the anti-inflammatory potency but also the degree of absorption of the steroid through its effeet on thymus weight. The test was performed using .Wistar or Sprague-Dawley rats of both sexes weighing about 60 g. The right ears of the rats were treated. with a phlogistic agent consisting of 4 parts pyridine, 1 part distilled water, 5 parts diethyl ether and 10 parts 4 per- These results show that the l7-valerate of 6a,9adifluoroprednisolone possesses a local antiphlogistic effect at least 25 times higher and a systemic effect 5 times higher than betamethasone l7-valerate. These properties differentiate the compound of this invention from the previously known topical anti-inflammatory agents.

EXAMPLE 3 An ointment having the following composition is prepared for external use following accepted pharmaceutical compounding procedures.

Components Percent By Weight 6a,9a-difluoroprednisolone l7-valerate 0.10

Beeswax 5.00

Anhydrous lanolin 5.00

White soft parafiin 20.00

Amphocerin K (Dehydag, Deutsche Hydrierwerke G.m.b.H.,Diisseldorf) 25.00

Liquid paraffin 14.90

Distilled water Melt the beeswax, the lanolin, the white soft paraffin and the liquid paraffin at 70 C, add theactive ingredient, then the mixture of the 'AmphocerinK and the water. Refine twice.

I EXAMPLE 4 l-lydrophilic ointment having the following composition;

cent croton oil in diethyl ether (v/v)- Control rats were treated with the above vehicle, topically applied to both sides of the right external ear via curved, felt tipped forceps, until the ear surfaces appeared uniformly moist. Test animals were treated with the same vehicle in which different amounts of the steroid under examination were dissolved. 6 hours later, when the phlogistic response to croton oil was maximal, each animal was lightly etherized and both ears were removed and individually weighed on a torsion balance. The antiphlogistic effect of the test steroid was expressed by the decrease in weight of the right ear. 48

hours after topical application of the materials, the

Components Percent By Weight :,9a-difluoroprednisolone 17-va1erate 0.300 Propylparab en 0.01 5 Methylparaben 0.025 Sodium laurylsulphate 1.000 Propylene glycol 12.000 55 Ste'aryl alcohol 25.000 White soft paraffin 25.000

animals were sacrificed and the thymi were removed and weighed on a torsion balance. The weight of the thymus was taken as an index of the systemic effect of the compound.

The results are reported in Table l.

Distilled water to 100% Melt the stearyl alcohol and the white soft paraffin on a steam bath, and warm to about C, add a solution of the active ingredient in the propylene glycol, then the other ingredients, previously dissolved in the water and warmed to 75 C. Stir the mixture until it congeals.

In the above hydrophilic ointment sodium laurylsulphate can be replaced by polyoxyl 4O stearate in an amount of 5 percent by weight.

EXAMPLE Componen Percent By Weight Cream having the following composition 6a,Qa-difluoroprednisolone l7-valerate 0025 Liquid paraffin 29.975 Components Percent By Weight 5 White soft paraffin 70.000

6a,Qa-difluoroprednisolone l7-valerate 0.050 P 12-000 Add the active product to the other ingredients, White soft paraffin 6.480 0 Liquid ffi @480 previously sterilized by heating at 120 C for an hour. p py Swarm 3-240 Refine twice and distribute into sterile tubes. Propylene glycol 3.240 Methylparaben 0. l 80 Propylparaben 0.050 EXAMPLE 8 Tween 80 0.200 pq h glycol 6000 4950 An ointment for external use IS prepared having the Distilled water 63.130 follow ng compos t on Melt the cetostearyl alcohol, the white soft paraffin, the liquid paraffin and the isopropyl stearate at about 70 C, add a solution of the active ingredient in the propylene glycol, then the other ingredients previously mixed with the water and warmed to 70 C. Refine twice.

Add the active product to the other ingredients, previously melted at 75 C and stir the mixture until it congeals.

EXAMPLE 7 Ophthalmic ointment having the following composition Components Percent By Weight 6a,9a-difluoroprednisolone l7-valerate 0.025 Lanolin 14.450 Liquid paraffin 17.750 Neomycin sulphate 0.400 White soft paraffin 67.375

Add the 6a,9a-difluoroprednisolone l7-valerate and the neomycin sulphate to the other ingredients previously melted at C and refine twice.

EXAMPLE 9 Lotion having the following composition Components Percent By Weight 6a,9a-difluoroprednisolone l7-valerate 0.03 Ethyl alcohol 50.00 Propylene glycol 20.00 Distilled water 29.97

Dissolve the active product in the alcohol and add to a clear mixture of the other ingredients.

We claim l. 6a,9a-Difluoroprednisolone l7-valerate.

UNITED STATES PATENT OFFICE CERTIFICATE UP QQEQTION Patent N 3.691.214 Dated Segtember 12, 1972 Inventor(s) Alberto Ercoli and Rinaldo Gardi It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 2, lines 30-40, the structural formula should be amended as follows:

I should be Poem o-mso (ac-s9) USCOMM-DC seam-pe h u 5 GOVERNMENT FRI DiT IiIG rustic: a; n-uz-Ifu UNITED STATES PATENT OFFICE CERTIFICATE 0E QQREECTEGN Patent No- 3,691,214 Dated September 12, 1972 Inventor(s) Alberto Ercoli and Rinaldo Gardi Page 2 It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 4, lines 1-13, in Table I, the second column should be amended as follows:

Right ear Right ear g g) wt. (mg) 121.2 -4.5 121.2 4.5 127.1 i 4.7 should be 127.1 1 4.7

118.3j 6.- ll8.3j;6.l

88.0 -I;3.9 88.0i3.9 87.3i5. 87.3i5.4 s5.9 2.3 85.9123

Signed and sealed this 13th day of November 1973,

(SEAL) Attest:

EDWARD M.FLETCHER,JR. RENE D. TEGTMEYER Attesting Officer Acting Commissioner of Patents FORM po'mso 069) USCOMM-DC scan-ps9 I h u.s. sovzmgrnk r r Hamil N6 amt; @959 o-sss-su 

